Apurinic endonucleases initiate the repair of apurinic/apyrimidinic (AP) ()sites, of which perhaps thousands per day are introduced into the human genome by spontaneous base hydrolysis and reactions with oxygen radicals and other cellular metabolites (Lindahl, 1993). If left unrepaired, the bypass of AP sites during DNA replication can result in mutations and loss of genetic integrity (Loeb and Preston, 1986). For example, yeast strains deficient in Apn1 (the major AP endonuclease of Saccharomyces cerevisiae) have a substantially elevated frequency of spontaneous mutations (Ramotar et al., 1991). The extra mutations arising in these repair-deficient yeast strains include all classes of single-base pair substitutions, but most dramatically transversions prompted by the loss of purines (Kunz et al., 1994).

Molecular studies of prokaryotic and eukaryotic AP endonucleases have revealed two families of proteins: those related to Escherichia coli endonuclease IV and yeast Apn1, or those related to E. coli exonuclease III and the major human AP endonuclease, Ape (Demple and Harrison, 1994). Both enzyme families are ``class II'' AP endonucleases, which hydrolyze the phosphodiester bond on the 5` of AP sites (Levin and Demple, 1990) to allow excision and repair DNA synthesis (Demple and Harrison, 1994). These AP endonucleases also remove 3`-phosphoglycolate esters and 3`-phosphates from oxidative strand breaks (Chen et al., 1991; Demple et al., 1986; Henner et al., 1983; Johnson and Demple, 1988; Winters et al., 1992, 1994). Although E. coli exonuclease III has a robust 3`-repair diesterase function (Demple et al., 1986), this is a minor activity of the homologous human Ape protein (Chen et al., 1991). The cDNA (Demple et al., 1991; Robson and Hickson, 1991; Seki et al., 1992) and the gene (Harrison et al., 1992) encoding the major human AP endonuclease have been isolated. The APE gene has five exons, one untranslated, and four introns, and is contained within a 3-kb segment of DNA located on chromosome 14q at position 11.2-12 (Harrison et al., 1992). The same gene was identified in independent cloning efforts as HAP1 (Robson et al., 1992; Zhao et al., 1992) and as APEX (Akiyama et al., 1994), and assigned to the same chromosomal site. No disease related to DNA repair has been directly linked to this genome locus. However, the importance of this repair enzyme is suggested by the increased sensitivity to HO or alkylating agents of rat glioma cells expressing of an antisense APE transcript (Ono et al., 1994).

APE and its protein product were also isolated in a screen for an activity that restores DNA binding activity to oxidized c-Fos and c-Jun proteins in vitro (Xanthoudakis et al., 1992). This ``Ref1'' activity was also found for a larger, related protein from the plant Arabidopsis thaliana (Babiychuk et al., 1994). The in vitro Ref1 activity seems to reside in a short segment of Ape outside the region homologous to exonuclease III and independent of the AP endonuclease function (Walker et al., 1993; Xanthoudakis et al., 1994).

Hypoxic conditions in colon cancer cells increased APE expression (Yao et al., 1994). Expression of APE is also transcriptionally modulated during regeneration of the epithelium after physical injury. ()We have therefore attempted to identify the cellular components that regulate expression of the APE gene. The work presented here identifies promoter elements and DNA-binding activities that mediate basal APE expression in cultured cells.

MATERIALS AND METHODS

Cell Culture

Chemical Agents

Protein and RNA Analysis

To determine the level of Ape activity, cells were harvested after washing with phosphate-buffered saline (PBS) and extracts prepared according to Chen et al.(1991). After treatment of HeLa cells with bleomycin sulfate or heat shock, S100 extracts were used to partially purify Ape using DE52 and Bio-Rex 70 chromatography, as described previously (Chen et al., 1991). Assays for 3`-repair diesterase were carried out according to Chen et al.(1990).

Transcription Start Site

Production of Promoter Constructs

Figure 1: Physical structure of the APE promoter. A, the 14-kb fragment encompassing the APE gene showing the restriction sites for XhoI (X), SmaI (S), HindIII (H), PstI (P), SacI (S1), and BamHI (B). B, the 4.1-kb HindIII fragment, which contains 65 bp of the first untranslated exon (). C, the region between the PstI and NruI sites, indicating potential recognition sites for Sp1, glucocorticoid receptor (GR), USF, and AP1. A potential CCAAT box is also situated in this region.

Transient Transfection

Mobility-shift Analysis

()

DNase I Footprinting Studies

RESULTS

Significant regulation of the APE gene in response to DNA-damaging agents has not been reported. In our hands, the amount of Ape protein or APE mRNA was not altered after treatment of HeLa cells with various DNA damaging agents: bleomycin sulfate, paraquat (a free radical generator), or heat shock (summarized in Table 1). However, our own recent work indicates possible transcriptional regulation of APE during epithelial wound healing, and the recently reported hypoxic response of APE (Yao et al., 1994) shows that APE transcription is regulated under some circumstances. We therefore analyzed the functional elements of the APE promoter.

Analysis of the 2-kb region upstream of APE (data not shown) for possible regulatory sequences (using the GenBank transcription factor data base) revealed several potential recognition sites for transcription factors within the 600 bp upstream of the start point of APE cDNA (GenBank accession no. M99703). These sites included potential binding sequences for Sp1, glucocorticord receptor, c-Myc-like proteins (Faisst and Meyer, 1992) such as upstream factor (USF; Sawadogo et al., 1988; Gregor et al., 1990), and AP1 (Fig. 1). In order to determine whether the AP1 or glucocorticoid receptor binding sites were biologically functional in the APE promoter, K562 or HeLa cells were treated with a phorbol ester (TPA) or dexamethasone. Although Northern analyses demonstrated strong induction of the 2.4-kb c-Fos mRNA after a 6-h TPA treatment, the level of the 1.5-kb APE message was not detectably altered during a 24-h exposure to TPA (Table 1). The APE mRNA also did not vary significantly following dexamethasone treatment (Table 1). Despite the response of APE to hypoxic conditions, incubation of K562 cells with the hydroxyl radical scavenger dimethyl sulfoxide (1.2% final concentration) did not change APE transcription (Table 1).

Transcriptional Start Sites

Figure 2: Transcription start sites for APE. A, primer extension was used to identify the transcriptional start sites of the APE mRNA in total RNA isolated from HeLa, HepG2, and K562 cells. Yeast tRNA was used as a negative control. The template DNA sequence is shown with the start site of the longest transcript indicated by +1. B, sequence of the region around the transcription start sites (coding strand). The three major, consistent start sites are underlined. The first major start site (+1) is 128 bp downstream of the putative CCAAT box (shown in bold). The intervening region also contains two consensus recognition sequences (CACGTG; shown in bold) for USF/Myc-like protein.

Identification of the APE Promoter Region

A 500-bp insert (in pCB22) had equivalent basal promoter activity to a 4-kb insert (in pCB2, Fig. 3A). Ligation of the 4-kb insert in the reverse orientation (pCB1) or deletion of 775 bp 5` to the transcriptional start site (pCB17) resulted in negligible CAT activity. No significant difference was detected between pCB22 and pCB11 (the latter plasmid containing a putative recognition sequence for AP1), which suggests that the segment downstream of the transcription start sites (+65 to +118) is not necessary for basal promoter activity.

Figure 3: Reporter gene constructs for the APE promoter. Individual plasmids (see text for construction) were transfected into HeLa cells together with pSVgal. After 48 h cells were harvested, extracted and assayed for -galactosidase and CAT activities. The ratio of CAT activity to -galactosidase was calculated and is expressed as a percentage of the ratio obtained for pCB22 in the same experiment. Each plasmid was transfected at least four independent times, using two different passages of HeLa cells. Symbols are as for Fig. 1. A, activity of promoter segments of 0.5-4.1 kb. B, activity of promoter segments deleted from -462 to -138. C, activity of promoter segments deleted from -138 to +65. D, effect of internal deletions on APE promoter activity.

Deletion of the region between -462 and -412, which contains a putative Sp1 recognition site, also did not alter basal promoter activity (Fig. 3B). In order to detect a significant decrease in basal promoter activity, it was necessary to delete the 5` terminus of the genomic insert to -138 (in pCB18), which expressed approximately half the CAT activity of pCB22 (Fig. 3B). The end point in pCB18 lies only 10 bp upstream of the CCAAT box. The region between -173 (pCB29) and -138 (pCB18) contains two overlapping Sp1 consensus recognition sequences (Fig. 4A) that may contribute to basal expression. As this paper was being finished, a report (Akiyama et al., 1994) appeared that confirms the results of Fig. 3(A and B).

Figure 4: DNA probes for protein binding studies with the APE promoter. A, the sequence shown between the AvaI sites was essential for APE basal promoter activity. Two overlapping Sp1 sites, three USF/Myc-like consensus sequences, and a CCAAT box-like sequence are shown in bold. Regions 1 and 2, which are underlined, are the sections of DNA protected by purified recombinant human Sp1 protein and HeLa nuclear extract, respectively (see Fig. 7). B, structures of probes I-IV used in protein binding studies. The hatchedboxes indicate the first exon of APE, and the numbering is relative to the first transcription start site (+1).

Figure 7: Nuclear protein-binding sites in the coding strand of the APE promoter. A, Sp1 binding studies. A 3`-labeled probe (containing the -173 to -26 region of the APE promoter) was incubated with the indicated amount of purified Sp1 protein and digested with 0.05, 0.10, or 0.15 units of RQ1 RNase-free DNase. The protected region shown corresponds to bp -169 to -148 of the APE promoter, which contains two overlapping Sp1 consensus recognition sites (see Fig. 4A). B, HeLa nuclear protein binding studies. The same probe as in A incubated with the indicated amount of HeLa nuclear extract and digested with 0.05, 0.10, or 0.15 units of RQ1 RNase-free DNase. The protected region shown corresponds to bp -130 to -105 of the APE promoter and encompasses the CCAAT box. A further region -141 to -131 also shows an alteration in the DNase I digestion pattern.

The deletion experiments showed that the basal APE promoter for HeLa cells is contained in a relatively small region of DNA. Therefore additional reporter gene constructs were prepared to determine the minimum region required for full promoter activity of APE. Little or no CAT activity was expressed with inserts of 53 or 87 bp of the APE upstream region (in pCB21 and pCB23, respectively, Fig. 3C). However, a fragment lacking the putative CCAAT box (-95 to +118) conferred 80% promoter activity relative to pCB22 in four independent transfections (Fig. 3C). Addition of the CCAAT box segment to pCB19 actually decreased the promoter activity consistently 2-fold. It seemed possible that the residual fragment in pCB19 might not accurately represent the APE promoter. Therefore, various internal deletions of pCB22, pCB11 and pCB10 were prepared (Fig. 3D).

All promoter activity was lost by deleting a segment between -210 and -25 (yielding pCB15), which contains the putative CCAAT box, the Sp1 site and a 64-bp segment that conferred promoter activity in pCB19 (Fig. 3C). Promoter activity was reduced 11-fold by deleting the CCAAT box and the Sp1 site (yielding pCB33). When another 43 bp were deleted from pCB22 (to generate pCB34), negligible amounts of CAT activity were expressed (Fig. 3D). This confirmed that promoter activity could be conferred by the region -98 to -55 within a larger genomic fragment. To test the role of this sequence in the context of the CCAAT box, plasmid pCB20 was constructed (Fig. 3D). Six independent transfections of each of the constructs shown in Fig. 3D, using three different passages of HeLa cells, consistently showed pCB20 to express higher levels of CAT activity than pCB22. These results can be contrasted with those for pCB18 and pCB19, which indicated significant promoter activity for the region downstream of the CCAAT box (Fig. 3C).

DNA Binding Studies

Figure 5: APE promoter binding by HeLa nuclear extracts. A, effect of increasing amounts of nuclear extract. Probes I-IV were labeled (see text) and incubated with 0, 1, 2, and 3 µg (probes II-IV) or 0, 1, and 3 µg (probe I) of HeLa nuclear extract in 50 µg/ml poly(dI-dC), for 20 min at room temperature. After separation in a 4% polyacrylamide gel, complexes were visualized by autoradiography. B, effect of poly(dI-dC). Probes I-III were labeled and, except for the first lane of each set, incubated with 3 µg of HeLa nuclear extract for 20 min at room temperature, in the presence of 50, 100, or 200 µg/ml poly(dI-dC). Labeled probe IV was incubated with 3 µg of extract (except for the first lane of this set) in 50 or 200 µg/ml poly(dI-dC).

In order to determine the contribution of USF and of Sp1 protein to the formation of these complexes, additional binding studies were carried out. The 64-bp region that conferred promoter activity in pCB19 (absent from pCB23; Fig. 3C), contains two consensus binding sites (CACGTG) for c-Myc-like proteins (Prendergast and Ziff, 1991), such as the human upstream factor (USF, Gregor et al., 1990; Fig. 4A). One site (TCACGTGA) is the sequence recognized by the major late transcription factor of adenovirus, of which USF is the human counterpart (Sawadogo et al., 1985; Carthew et al., 1985; Miyamoto et al., 1985). To test for the binding of this protein, we employed specific antibodies. Labeled probe I was incubated with HeLa nuclear extract and polyclonal anti-USF antiserum added to the reactions. Of the two complexes formed, one (the upper complex; Fig. 6A) decreased in intensity with increasing antibody concentration as a series of complexes of slower mobility appeared (Fig. 6A). Neither the second complex formed with probe I nor those formed with probes III and IV were affected by the anti-USF antibody (Fig. 6A). Although it is possible that the binding of other proteins to probe III may have masked the crucial epitopes in bound USF, the formation of a similar mobility complex with probe IV (lacking the USF site; Fig. 4) argues against this interpretation.

Figure 6: USF and Sp1 binding to the APE promoter. A, ``supershift'' by anti-USF antibodies. Probes I, III, and IV were labeled and incubated with 3 µg of HeLa nuclear extract at 50 µg/ml poly(dI-dC) for 5 min at room temperature. Polyclonal anti-USF antiserum was then added to yield a final dilution of 10, 5 10, 2.75 10, and 10 for probe I, or 5 10 and 10 for probes III and IV. Probe alone is indicated by ``-''. After another 15 min, protein-DNA complexes were analyzed as described in the legend to Fig. 5. No complexes were observed with any probe incubated with the antiserum alone (data not shown). B, binding of purified Sp1. Labeled probe III was incubated with 0, 50, and 150 ng of purified recombinant human Sp1 protein in 50 µg/ml poly(dI-dC) and 100 µg/ml bovine serum albumin, for 20 min at room temperature. In some incubations with 100 ng of Sp1 protein, an unlabeled double-stranded oligonucleotide containing the consensus Sp1 recognition site (Promega) was added (0.0175 or 1.75 pmol; rightmostlanes).

Incubation of pure Sp1 protein with probe III yielded two complexes, one of which was less intense and had slower mobility (Fig. 6B). Since this Sp1 site consists of two overlapping recognition sites, the upper band in Fig. 6B may correspond to the binding of a second Sp1 molecule to this second site. The binding by pure Sp1 was competed by a double-stranded synthetic oligonucleotide containing the Sp1 consensus sequence; a 20-fold molar excess diminished probe III binding significantly, and a 2000-fold excess eliminated it (Fig. 6B). Such competition was not observed for binding of HeLa nuclear extract protein(s) to probe III, although those extracts contain Sp1 that binds the synthetic oligonucleotide (data not shown).

Pure Sp1 formed a distinct footprint spanning the base pairs -169 to -148 in the APE promoter, as revealed in DNase protection experiments (Fig. 7A; for sequence see Fig. 4A). However, such a distinct footprint was not observed after incubation with HeLa nuclear extract (Fig. 7B), which instead had strongest binding activity for a 40-bp region containing the CCAAT box (Fig. 7B; for the sequence, see Fig. 4A). A partial protection of the USF site and adjacent 3` sequences may also occur (Fig. 7B). Addition of 50 ng of Sp1 protein to 30 µg of nuclear extract still did not result in a distinct Sp1 footprint (data not shown). Thus, although both USF and Sp1 are available in our nuclear extract, and the respective DNA sites are capable of binding these proteins, the binding of one or more other nuclear proteins over the CCAAT box region prevents USF and Sp1 from efficiently binding their DNA targets.

DISCUSSION

The APE gene product is expressed constitutively at relatively high levels in the nuclei (Demple et al., 1991) of transformed cells such as HeLa cells, Chinese hamster ovary cells, or HPB-ALL T-lymphoblasts (7 10 molecules/cell; Chen et al., 1991). Conversely, attempts to modulate the expression of this probable DNA repair protein by DNA-damaging treatments have yielded consistently negative results (Table 1). Such experiments have not been reported for untransformed human fibroblasts, in which the Ape levels are 10-20 times lower (Chen et al., 1991). A rather small upstream region (140 bp) of APE seems to be required for the high basal expression in HeLa cells, as shown here by deletion analysis of the APE promoter linked to a reporter gene.

Within this basal APE promoter lie several potential regulatory sites. Surprisingly, deletion of the putative CCAAT box of the APE promoter failed to obliterate transcriptional activity (in pCB19 and pCB33). This expression could result from promoter elements that remain silent when the CCAAT box is present, as may be the case with the USF-binding site (see below).

It is not known whether the altered constructs direct the use of the same transcriptional starts employed for basal expression by the intact APE promoter in HeLa, HepG2, or K562 cells. Like many TATA-less genes (Konecki, et al., 1992; Yoshimura et al., 1991; Yue at al., 1993), APE displays multiple transcription start sites, with those identified here clustered 130 bp upstream from the first splice junction (Harrison et al., 1992). Additional initiation sites for APE mRNA in HeLa cells were seen in some of our experiments (data not shown), and still other sites have been reported from other laboratories (Zhao et al., 1992; Robson et al., 1992; Akiyama et al., 1994). It remains to be seen whether these same sites are used during the induction of APE transcription in hypoxic cells (Yao et al., 1994) or possibly during epithelial regeneration.

Potential binding sites for transcription factors are present in the APE promoter (e.g. Sp1 and USF) and within the structural gene (e.g. AP1; Fig. 1). The AP1 site in exon 1 seems not to exert an effect in K562 cells, as suggested by the lack of response of APE transcription to TPA (Table 1). Similarly expression of the rat homolog of APE was not altered with c-fos induction in the hypothalamus after light exposure (Rivkees and Kelley, 1994).

Sp1 sites located -420 bp and -168 bp 5` of APE may make modest contributions to the basal expression, although at least one of these sites was evidently not strongly bound by Sp1 in HeLa nuclear extracts, even though the site 30 bp 5` of the CCAAT box is bound by pure Sp1 protein in vitro. The nuclear extracts also contained functional USF protein that could bind a cognate site in a DNA fragment lacking the CCAAT box, as judged by the ``supershifting'' effect of polyclonal anti-USF antiserum. Some binding was detected overlapping the USF site (40 bp 3` to the CCAAT box) with HeLa nuclear extracts and a hypersensitive site is situated at -69, just 3` to this region (Fig. 7B, and data not shown), but the lack of ``supershifting'' by anti-USF antiserum suggests that this binding does not involve USF itself.

The CCAAT-containing fragments exhibited strong and specific binding of nuclear protein(s) and the protection of a 40-bp region, including the CCAAT box itself. It seems possible that the latter binding represents recognition by basal transcription factor(s) in HeLa extracts, such as CP1 (Chodosh et al., 1988), NF-Y (Dorn et al., 1987), and CP2 or NF-1 (Chodosh et al., 1988). If so, such binding evidently precludes interaction with either USF or Sp1 at their nearby sites. In the absence of the CCAAT box, USF can bind its site and may contribute to the promoter activity of pCB19 and pCB33 (Sawadogo and Roeder, 1985; Sawadogo et al., 1988; Roy et al., 1991).

The APE promoter bears some features in common with so-called ``housekeeping'' genes: lack of a TATA box, multiple transcription start sites (Konecki et al., 1992; Yoshimura et al., 1991; Yue et al., 1993), and similar expression in a variety of tissues ()(Akiyama et al., 1994). Such widespread expression suggests the action of transcription factors present in many cell types and active under a variety of conditions. Nonetheless, APE transcription does increase in response to hypoxia in cultured carcinoma cells (Yao et al., 1994) and may be modulated during epithelial wound healing. It will be of interest to determine whether and how the protein binding sites observed here and the functional regions of the APE promoter might be employed during these regulated responses.

FOOTNOTES

*

This work was supported in part by American Cancer Society Grant CN-86 (to B. D.) and National Institutes of Health Grant GM40000 (to B. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked ``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§

Recipient of an National Research Service Award from the United States Public Health Service.

¶

To whom correspondence should be addressed.

()

The abbreviations used are: AP, apurinic/apyrimidinic; kb, kilobase pair(s); bp, base pair(s); DMEM, Dulbecco's modified Eagle's medium; TPA, 12-O-tetradecanoylphorbol-13-acetate; PBS, phosphate-buffered saline; USF, upstream factor.

()

L. Harrison, T. Galonopoulos, A. G. Ascione, H. N. Antoniades, and B. Demple, manuscript in preparation.

()

M. Sawadogo, personal communication.

()

L. Hughes-Davies, T. Galonopoulos, L. Harrison, M. Maxwell, H. N. Antoniades, and B. Demple, submitted for publication.

ACKNOWLEDGEMENTS

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